Issue: July 2020
Disclosures: Bass, Calabrese, Liew and Thanarajasingam report no relevant financial disclosures. Tarhini reports contracted research for Bristol-Myers Squibb, Genentech-Roche, Merck and OncoSec, and consulting/advisory board participation with Array Biopharma, BioNTech, Bristol-Myers Squibb, EMD Serono, Genentech-Roche, Immunocore, Merck, NewLink Genetics, Novartis, Partner Therapeutics, Pfizer and Sanofi-Genzyme/Regeneron.
July 17, 2020
13 min read

Walking the tightrope: Balancing tumor response, adverse events of checkpoint inhibitors

Issue: July 2020
Disclosures: Bass, Calabrese, Liew and Thanarajasingam report no relevant financial disclosures. Tarhini reports contracted research for Bristol-Myers Squibb, Genentech-Roche, Merck and OncoSec, and consulting/advisory board participation with Array Biopharma, BioNTech, Bristol-Myers Squibb, EMD Serono, Genentech-Roche, Immunocore, Merck, NewLink Genetics, Novartis, Partner Therapeutics, Pfizer and Sanofi-Genzyme/Regeneron.
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Time moves in funny ways in medicine. Physicians and researchers can work for decades in obscurity on a cure for a particular disease and make little progress. But once the critical breakthrough comes, 6 months or a year can change everything.

In a 2018 feature, Healio Rheumatology outlined the nascent phenomenon of immune-related adverse events associated with cancer checkpoint inhibitor therapy. Two years later, it is time to look in again to see how far the field has come.

For rheumatologists managing irAEs, preserving the patients oncologic response to treatment often takes precedence, noted David Liew, FRACP. It is not a space we own by ourselves. We have to walk the tightrope between minimizing the tumor and making sure the rheumatic event is tolerable.
For rheumatologists managing irAEs, preserving the patients oncologic response to treatment often takes precedence, noted David Liew, FRACP. It is not a space we own by ourselves. We have to walk the tightrope between minimizing the tumor and making sure the rheumatic event is tolerable.
Source: Austin Health.

“In the last couple of years, we have come up with some answers in what to do with irAEs,” David Liew, FRACP, in clinical practice and a research fellow in the department of clinical pharmacology and therapeutics at Austin Health in Melbourne, Australia, said. “But make no mistake, the field is still in its infancy, and there are still more questions than answers.”

Anne R. Bass, MD, professor of clinical medicine at Weill Cornell Medicine and rheumatology fellowship program director at the Hospital for Special Surgery, discussed a surprising irony that has plagued this subspecialty. “Rheumatology was probably the last field to get on board, strangely enough,” she said in an interview. “Oncologists recognized the problem, but it took a while for rheumatologists to be called in.”

One reason for this is that since the first checkpoint inhibitor was only approved in 2011, no one has even a decade of real-world experience with programmed cell death protein (PD)-1, programmed death-ligand (PDL)-1 and cytotoxic T-lymphocyte-associated protein (CTLA)-4 blockers, the mainstays of the approach.

Anne R. Bass, MD
Anne R. Bass

Another reason is that oncologists do not routinely examine joints, so checkpoint inhibitor-related arthralgias often go unnoticed and, consequently, are not referred to rheumatology, according to Bass. There is better recognition of other common irAEs such as colitis and pneumonitis, as those events can be lethal. Accordingly, there are more data for those events, as well — but the data on irAEs, overall, remain sparse.

Liew offered one other explanation for why it took so long for rheumatology to be looped in. “It is not a space we own by ourselves,” he said. “For everything we do, we have to consider the needs of oncology.”


The meaning of this is simple: the primary aim of irAE management is preserving oncologic response. “We have to walk the tightrope between minimizing the tumor and making sure the rheumatic event is tolerable,” Liew said. “Len Calabrese likes to use the word ‘equipoise,’ and I think that is the most appropriate term.”

With this goal of equipoise in mind, treatment paradigms are evolving, largely as a shift from steroids to biologics. Oncology and rheumatology now routinely work in tandem, but communication remains imperfect. The next 2 years might bring about changes that will dramatically alter the field, but there is still considerable work to be done.

Understanding Pathogenesis

For Ahmad A. Tarhini, MD, PhD, director of Cutaneous Clinical and Translational Research, and leader of the Cutaneous Neoadjuvant and Adjuvant Translational Science Program at H. Lee Moffitt Cancer Center and Research Institute, the ball cannot move forward until one fundamental question is answered. “The exact pathogenesis of these events continues to be unclear,” he said. “There is evidence that it is associated with Th-17 pathway activation and high levels of IL-17, but we do not yet have reliable predictors that can tell us which patients are likely to experience these events. It is an open question.”

Ahmad A. Tarhini, MD, PhD
Ahmad A. Tarhini

That question is being investigated, albeit piece by piece. “We know that, histologically, immune-related colitis is similar to inflammatory bowel disease,” Tarhini said. “When looking at biopsy specimens, we see lymphocytic and neutrophilic infiltration, which is similar to what we see in patients being treated with immune checkpoint inhibitors.”

These clues are pointing researchers in the direction of human leukocyte loci associated with various immune disorders, including type 1 diabetes, according to Tarhini. “We are gradually learning about these associations that warrant further investigation,” he said.

Link Between Tumor Response, irAEs

Even for a question that would seem to have a relatively simple answer — Do patients who develop irAEs have an improved oncologic response compared with patients who do not experience these events? — the answer may not be so simple.

In their study in BMC Medicine, Zhou and colleagues conducted a meta-analysis of 30 studies and nearly 5,000 patients to determine whether irAEs correlate with the efficacy of checkpoint inhibition. Results showed that compared with patients who did not develop an irAE, those with irAEs experienced improved overall survival (HR = 0.54; P < .001) and progression-free survival (HR = 0.52; P < .001).


The general interpretation of such a data set is that the presence of an immune-related event means the immune system is activated, and, therefore, working against the tumor as oncologists might hope. But not everyone is convinced that this is the case.

“Does getting an irAE lead to a better prognosis for a patient?” Uma Thanarajasingam, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., said in an interview. “We have observed this in some small cohorts, but I do not think the answer is clear as yet.”

Uma Thanarajasingam, MD
Uma Thanarajasingam

The answer is unclear, at least in part, because when treatment of the irAE is factored into the equation, the picture grows muddier.

This was demonstrated by Verheijden and colleagues, who assessed associations between PD-1 and/or CTLA-4 blockade and overall survival (OS) in 1,250 patients with advanced melanoma in a study published in Clinical Cancer Research. Results showed that severe toxicity was associated with an increase in survival, with a median OS of 23 months for patients with severe toxicity and 15 months for those without (HR = 0.77; 95% CI, 0.63 to 0.93).

However, among patients with severe toxicity, those treated with anti-TNF therapy with or without steroids for steroid-refractory toxicity had reduced survival compared with patients treated only with steroids (HR = 1.61; 95% CI, 1.03 to 2.51). The group arrived at the confounding conclusion that the possible benefit of an irAE is “abrogated” by TNF inhibition.

“This study showing that TNF inhibitors worsened survival was retrospective and flawed in many ways,” Bass said. “But it has given us pause.”

The question for Tarhini comes back to the underlying mechanisms. “It is important to understand if patients have inherent risk factors or conditions that predispose them to developing certain immune-related events,” he said.

There is a simple explanation why it is taking so long to answer these questions, according to Bass. “The patient numbers are small,” she said. “The only places where there are enough patients to do these trials are big cancer centers like Dana Farber or Memorial Sloan Kettering.”

But even at those facilities, there is one other hurdle to deeper understanding of irAEs. “They are run by oncologists who are obviously not as interested in rheumatic adverse events as they are in monitoring anti-tumor activity,” Bass said. “And even at these places, when less than 5% of patients experience arthritis or arthralgias, you are just not going to get the numbers to do a clinical trial that is adequately powered.”


In the absence of prospective trials, then, rheumatologists must make do with trying to find the signal in the noise of retrospective cohort studies and case series. But rheumatology is used to making do with few data, and so specialists in the field are forging ahead as best they can.

Emerging Guidance

Perhaps the best indicator that this subspecialty is poised to take a big step forward is the recent publication of EULAR recommendations for managing irAEs associated with checkpoint inhibitor therapy. Karolina Benesova, MD, of the department of hematology, oncology and rheumatology at the University of Heidelberg, in Germany, presented the document on behalf of a task force of 23 experts at the recent EULAR E-Congress.

The paper contains four over-arching principles and 10 recommendations, with key principles stressing collaboration with oncology and preservation of anti-tumor response. Looking closer at the actual recommendations, clinicians are urged to be aware of the wide spectrum of presentations of irAEs and to consult rheumatology at first suspicion of a rheumatic event.

“Reports on the clinical features of rheumatic irAEs show that these can resemble the full spectrum of known rheumatic and musculoskeletal disease,” Benesova said. “However, usually, irAEs have an atypical or incomplete presentation.”

Comprehensive assessment of these patients should be performed, with metastases, paraneoplastic syndromes and unrelated rheumatic diseases as part of the differential diagnosis. While management of rheumatic diseases is often aggressive, Benesova said that the task force prefers a “defensive strategy” in managing irAEs.

But even Benesova acknowledged that the evidence base from which the task force drew was limited. “Future trials should aim at closing these gaps,” she said. “Updates will likely be required.”

“I applaud EULAR for these guidelines, but it must be noted that the grade of evidence is C and D because we still have not accrued enough high-grade evidence over the last 2 years to support our clinical decision-making,” Thanarajasingam said. “It is worth highlighting, though, that we had no evidence 2 years ago to even write a paper like this. Maybe in another 2 years, we will have grade A or B evidence.”

Moving Away From Steroids

If there is an area that is generating the most evidence, it pertains to the use of steroids in managing irAEs. The EULAR recommendations stipulate that glucocorticoids should be considered as first-line therapy for these events. However, Benesova noted that a low dose is optimal. “More than 10 mg prednisone daily should not be used,” she said.


A key study in this area was conducted by Faje and colleagues, who investigated whether high-dose glucocorticoids for the treatment of ipilimumab- (Yervoy, Bristol-Myers Squibb) induced hypophysitis reduced survival outcomes in melanoma. In a cohort of 98 patients, results showed that OS (HR = 0.24; P = .002) was lower and time to treatment failure (HR= 0.28; P = .001) was longer in the low-dose group compared with the high-dose group.

“Previous studies, before the findings from Faje et al, showed that a high dose of steroids did not impact oncologic outcomes,” Bass said. “So, their results were kind of an eye opener.”

Cassandra Calabrese, DO
Cassandra Calabrese

In an interview with Healio Rheumatology, Cassandra Calabrese, DO, of the Cleveland Clinic, noted that while glucocorticoids remain the cornerstone of treatment of irAEs, there has been a shift toward more targeted therapies. “This is being done in an attempt to maximize efficacy of immunotherapy, gain better control of the irAE as well as avoid long-term side effects of glucocorticoids,” she said.

“We are at the point where we are realizing that steroids are not always benign in these patients,” Liew added. “As a result, we are far more cautious about steroids than we were 2 years ago, and that trend may continue.”

Liew believes that development of treatment paradigms for conventional rheumatic diseases and for irAEs is analogous. “We used to have a really high tolerance for high doses of steroids, and we used to allow patients to bear the brunt of the toxicity,” he said. “Over time, we have come to recognize the importance of low to moderate steroid doses. This is one area where we have more data, and have consequently improved, since 2018.”

In managing irAEs, rheumatologists have learned many lessons about the use of corticosteroids and other immunosuppressants. “One is that a minority of patients with irAEs are refractory to corticosteroids, and require additional immunosuppression such as TNF blockers to control a severe irAE,” Tarhini said. “Another is that if we are anticipating that steroid therapy will be prolonged, we use prophylactic antibiotics to mitigate infection risk.”

Data are beginning to support the shift away from steroids. In their study in Journal for ImmunoTherapy of Cancer, Abu-Sbeih and colleagues conducted a retrospective review that included 179 patients who developed immune-mediated colitis. While 84 patients had been treated with 4 to 6 weeks of first-line steroids, results showed that earlier intervention with non-steroidal immune therapy was associated with fewer hospitalizations (P = .03), less likelihood of steroid taper failure (P = .03), fewer steroid tapering attempts (P < .01), a shorter course of steroid treatment (P = .09) and had a shorter duration of symptoms (P < .01).


“Observational studies have shown that when we shift to other therapies, patients get less steroids, and that is generally a good thing,” Bass said. “They also may get better faster, and that is a good thing. But we still do not have good, prospective studies to prove this, so there is still work to be done.”

Shifting to TNF Inhibitors

Further recommendations from the EULAR document address the shift away from steroids, stipulating that steroid therapy should be followed by conventional synthetic DMARDs, then biologic DMARDs. TNF or IL-6 inhibitors are the recommended biologic approaches.

Looking at specific results that underscore this recommendation, Perez-Ruiz and colleagues wrote that while combination therapy using PD-1 inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab has shown efficacy in melanoma, renal cell carcinoma and non-small-cell lung cancer, frequent and serious irAEs — including autoimmune colitis — have been reported. Their mouse model showed that concomitant administration of available TNF inhibitors with this immunotherapy combination may mitigate colitis while simultaneously improving anti-tumor activity.

Liew used the word “unlock” to describe the way TNF inhibitors work in concert with certain checkpoint combinations. “Results from this mouse model open up the possibility that we are, in fact, doing patients a favor by giving them TNF inhibitors,” he said. “This certainly may be true in melanoma.”

Gastroenterologists have been using adalimumab (Humira, AbbVie) and infliximab (Remicade, Janssen) on an as-needed basis to shut down colitis, which is still part of some treatment algorithms for colitis as an irAE, according to Thanarajasingam. “That is where TNF inhibitors are most broadly used in irAEs,” she said.

While approaches like this are gaining acceptance, Thanarajasingam highlighted the key reason TNF inhibitors have not become standard of care in irAEs. “Some of these data are certainly compelling, but I cannot point you to any large cohorts of patients or longitudinal, prospective data that support it,” she said.

Looking Ahead to IL-6

If another target beyond TNF inhibition is going to rise to prominence as an irAE management tool in the next 2 years, it is likely to be the IL-6 pathway.

“I am seeing increasing and ongoing interest in biologics, including IL-6 inhibitors, particularly for the most common type of irAEs: inflammatory arthritis,” Thanarajasingam said. “Personally and anecdotally, talking to both patients and colleagues, one general trend is that there is more comfort among oncologists with IL-6 inhibitors. But it is unclear why.”

Calabrese also suggested a level of comfort with IL-6 inhibitors to treat inflammatory arthritis and polymyalgia rheumatica-like clinical phenotypes from checkpoint inhibitor therapy. However, as with other areas under the irAE umbrella, there is one primary concern: limited data.


It is worth noting that Bass feels as though the oncology community has less comfort with IL-6 inhibition. “I see this particularly among clinicians treating patients who have failed TNF inhibitors,” she said.

There are case series for IL-6 inhibition, and prospective trials are underway, according to Liew. “There is definitely real promise there,” he said. “But there is just a little less familiarity with using drugs like tocilizumab [Actemra, Genentech].”

In the absence of both familiarity and data, experts like Calabrese are hoping to close knowledge gaps and help guide clinicians in making effective choices for their patients with irAEs. In a review first-authored by Khashayar Esfhani in Nature Reviews Clinical Oncology, Calabrese and colleagues proposed a personalized immunohistopathologically guided process for choosing the appropriate treatment regimen beyond first-line corticosteroids.

“Immunomodulatory treatments can have organ-specific toxicities overlapping with the sites affected by irAEs,” the researchers wrote. “They can also be associated with an increased risk of serious infections and possible blunting of effects from immune checkpoint inhibitors.”

The hope is that understanding the risks and the impact on oncologic response will lead to better overall management of irAEs.

Roadmap for the Future

With the EULAR recommendations in place, and experts prospectively studying the spectrum of therapies for managing these events, the next 2 years could bring about real change in the field.

Beyond the particulars of therapeutic interventions, Tarhini stressed that patient safety also should guide the management of irAEs moving forward. “Remember, they can be fatal in up to 2% of patients,” he said.

Grading these toxicities is the best way to mitigate this mortality risk, according to Tarhini. “If it is grade 1 and you can do symptomatic management, that is where you start,” he said. “If it is more persistent, it becomes grade 2 and you go to a moderate dose of steroids.”

Events of grade 3 or 4 should be treated first with a high dose of steroids before moving to biologic therapies. “The goal is to work across this valance of immunosuppression and minimizing risk,” Tarhini said.

All of these points are underscored by the seventh recommendation from the EULAR document, which stipulates that the decision to cease or continue checkpoint inhibitor therapy should be based on the severity of the irAE, the extent of immunosuppression required to manage it, tumor response and the future oncology treatment plan.

If there is a final piece of the puzzle, it is ongoing collaboration between and across specialties, according to Calabrese. “These patients need to be seen yesterday, not in 3 weeks,” she said, and added that an open line of communication between oncology and rheumatology is critical.


“In February 2020, we held the first of its kind, multidisciplinary CME clinical conference on management of toxicities from immunotherapy,” Calabrese said. She encouraged clinicians to pay attention to these activities, and to visit the ACR’s abstract archive to learn more about irAEs. “Last year, there were over 60 abstracts presented on the topic, and this year I expect there will be many more than that, in addition to a study group.”

Whether that number will double, triple, or stay the same in subsequent ACR meetings remains to be seen. But what is certain is that there are plenty of topics to investigate. “We do not yet have good biomarkers for these events,” Liew said. “We do not have good screening or classification tools. These are the things that we, as rheumatologists, need to build in order to care for these patients.”